This is a competitive renewal to provide the major source of salary support for the applicant, Mary-Jeanne Kreek, M.D., as a senior Research Scientist Awardee (and also as a Principal Investigator and Scientific Director of an NIH-NIDA Treatment-Related Research Center.) This award will allow the applicant to continue to spend the majority of her time in basic laboratory-based and basic clinical research, as well as to continue to spend a significant amount of time in scientific training and mentoring in the graduate, postgraduate, and mid-career levels, as well as science education at the undergraduate, graduate and high school levels. The applicant will also continue to be active in science education, particularly as pertains to the biological basis of the addictive disease, to a more general public. The most effective treatments for the addictive diseases, including opiate addiction, cocaine addiction, alcoholism, and nicotine addiction, probably will continue to be based on a fundamental understanding of the biological and molecular bases of addictive diseases; the physiologic and pharmacologic effects of drugs of abuse, and of agents used for the treatment of specific addictions, and also of medical and behavioral problems which frequently coexist with specific addictions and may complicate treatment, such as HIV-1 (AIDS), hepatitis B, and especially hepatitis C. Research activities will continue to identify and study the biological correlates of addictive diseases, factors which affect treatment outcome, and primarily the molecular neurobiological basis of addiction, and the human molecular genetics of addictions. There will be four domains of Specific Aims: 1) Laboratory-based research (Projects 1, 2 and 3); 2) Basic clinical research (Project 4); 3) Human molecular genetics (Project 5); and, 4) Applied clinical research (Project 6), each related to four specific addictions: opiate (primarily heroin) addiction, cocaine addiction, alcoholism, and nicotine addiction. Three specific projects within these four Specific Aims are, e.g.: 1) Effects of chronic opiates and cocaine, withdrawal, and challenge on receptors, and gene expression of the endogenous opioid and related neurotransmitter systems; 2) Effects of opiates and cocaine on the molecular biology and expression of the stress responsive hypothalamic-pituitary-adrenal axis; 5) Human genetics research of addictions with emphasis on studies of the human molecular genetics.